Many drugs are compounded for delivery by methods that result in a therapeutic effect in the body of a human or other mammal that varies considerably over time. Drugs delivered by intravenous routes may result in a nearly instantaneous peak in blood plasma drug concentration, followed by a gradual decay in blood plasma level as the drug is metabolized. Drugs that are delivered by oral or intramuscular routes may result in a blood plasma concentration of the drug that increases slowly during systemic uptake of the drug, followed by a decrease from peak plasma drug levels. Drug dosing may need to be repeated at frequent intervals, such as daily, but this at best only approximates a continuous or constant therapeutic level.
It would be beneficial to deliver many types of therapeutic agents in a delivery system that provides for sustained release of the agents over an extended period of time. A variety of polymers used for controlled release and delivery of drugs have been developed in the past 20 years. Most of the polymers are formed into implants or injectable microspheres. Such polymers are, and must be, biodegradable and biocompatible. In order to produce suitable forms of polymers, complicated fabrication processes are required that typically involve organic solvents. The use of organic solvents, however, may cause denaturation of some protein drugs, and even traces of an organic solvent may be toxic.
Polymer hydrogels have been explored for drug delivery and controlled release. For example, chemically cross-linked polymer hydrogels have been used as implants. Some injectable drug delivery systems form chemically cross-linked hydrogels in the body after injection, providing a drug depot. However, the chemical reactions occurring in the body due to the presence and/or breakdown of some of these polymers may cause tissue irritation and damage.
Physical polymeric hydrogels have been widely explored for biomaterials applications. Examples include hydrogels formed by complexation of enantiomeric polymer or polypeptide segments, and hydrogels with temperature- or pH-sensitive properties. They attract special attention for controlled drug delivery because of the mild and aqueous conditions involved in trapping delicate bioactive agents such as proteins. For example, in situ formed hydrogels formed from thermosensitive block copolymers have also been proposed as sustained release matrices for drugs. They have the advantage that there is no chemical reaction involved in the gel formation. These copolymer hydrogels are usually designed for macromolecular drugs such as proteins and hormones. The disadvantage of such temperature sensitive hydrogels is the practicality of using such a gel in injection.
More recently, amphiphilic block copolymers have attracted special interest for fundamental research as well as applications because of their unique chain architectures and physical properties in solid state as well as in solutions. Forster, S. et al., Adv. Mater. 10:195-217 (1998); Alexandridis, P. Curr. Opin. Colloid Interface Sci. 1:490-501 (1996). They have been extensively studied as building blocks in supramolecular polymer chemistry for highly ordered self-assembled structures. Forster (1998), Alexandridis (1996); Vanhest, J. et al., W. Science 268:1592-1595 (1995); Jenekhe, S. et al., Science 283:372-375 (1999); Kukula, H. et al., J. Am. Chem. Soc. 124:1658-1663 (2002). Amphiphilic block copolymers have been considered as biomaterials that take advantage of this self-assembly. The studies have resulted in biomaterials with novel macroscopic properties, which are used for controlled drug delivery and tissue engineering. Jeong, B. et al., Adv. Drug Delivery Rev. 54:27-51 (2002); Kissel, T. et al., Adv. Drug Delivery Rev. 54:99-134 (2002).
Poly(ethylene oxide) (PEO) is widely used as a hydrophilic and biocompatible polyether. Herold, D. et al., Biochem. Pharmacol. 38:73-76 (1989). Amphiphilic ABA triblock copolymers including PEO as the hydrophilic segment have previously been studied and described for use as biomaterials. The term ABA is used herein to refer to a polymer including a center segment of a first polymer, referred to as a B block polymer, and first and second end segments of a second polymer, referred to as an A block polymer. As a typical example, commercially available poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO, Pluronics™) triblock copolymers have been extensively studied in terms of their phase behavior and potential application for drug delivery. Alexandridis, P. et al., Colloids Surf. 96:1-46 (1995); Bromberg, L. et al., Adv. Drug Del Rev. 31:197-221 (1998). Recently, more attention has been focused on amphiphilic ABA triblock copolymers of PEO with biodegradable polyesters. Synthesis and characterization of triblock copolymers consisting of PEO and polyesters such as poly(L-lactic acid) (PLLA), poly(glycolic acid) or their copolyesters have been reported. Jeong, B. et al., Nature 388:860-862 (1997); Jeong, B. et al., Macromolecules 32:7064-7069 (1999); U.S. Pat. No. 5,384,333; U.S. Pat. No. 5,702,717; U.S. Pat. No. 4,716,203; U.S. Pat. No. 5,476,909. Such amphiphilic block copolymers tend to form micelles or even gels in water, which are potentially useful for injectable drug delivery systems.
Another interesting hydrogel system consists of polyrotaxanes created by linear polymers such as poly(ethylene oxide) (PEO) penetrating the inner cavity of cyclodextrins (CDs) to form inclusion complexes with a necklace-like supramolecular structure. Harada A. et al., Nature 356:325 (1992); Li J. et al., Polym. J. 26:1019 (1994). However, only high molecular weight PEO can form hydrogels with α-CD, and the dissociation of the hydrogel in aqueous solution is rapid because of the hydrophilic nature of PEO.
Injectable drug delivery systems using related hydrogels are disclosed in US Patent Application 2002/0019369 A1, in the name of inventors Li et al., entitled Injectable Drug Delivery Systems with Cyclodextrin-Polymer Based Hydrogels, the disclosure of which is hereby expressly incorporated by reference. This application discloses cyclodextrin polymer-based injectable compositions formed from CD, a polymer that is poly(ethylene glycol) (PEG), a PEG derivative, or a PEG copolymer, and a drug. Reference is made to the use of poly(propylene glycol) or other poly(alkylene glycols) as the polymer in the system. While the polymer hydrogels disclosed in this publication provide promising sustained release systems, they have not been demonstrated to provide optimized release kinetics for sustained release of longer than one week.
Poly[(R)-3-hydroxybutyrate] (PHB) is an optically active biodegradable polyester synthesized as a carbon and energy storage material by many microorganisms. Doi, Y. Microbial Polyesters; VCH Publisher, New York (1990).
U.S. Pat. No. 5,702,717 to Cha et al. discloses thermosensitive biodegradable copolymers made up of a hydrophobic A polymer block that may is a poly(α-hydroxy acid) or a poly(ethylene carbonate), and a hydrophilic B polymer block that is a poly(ethylene glycol). These polymers are disclosed for drug delivery, and are characterized as exhibiting a reverse thermal gelation behavior. A disclosed list of potential examples of poly(α-hydroxy acid) polymer blocks includes hydroxybutyric acid; however this is a poly(β-hydroxyalkanoate), and does not fall within the polymer class taught by Cha et al., nor would it likely exhibit all of the characteristics sought by Cha et al. Further, Cha et al. utilize a synthesis process that entails ring-opening polymerization of cyclic monomers, which may result in potentially undesirable racemization of the poly(α-hydroxy acid)s.